INVESTIGATING THE ROLE OF ALPHA SYNUCLEIN IN MITOCHONDRIAL DYSFUNCTION USING IPSC-DERIVED INDUCED NEURONS

Abstract

Elevated expression or misfolded alpha synuclein has been associated with mitochondrial dysfunction in the pathology of synucleinopathies and Parkinson’s disease. However, the underlying mechanism arising from altered alpha synuclein expression leading to the disruption of normal mitochondrial functions remain unclear. In our studies, we investigated this intricate relationship between alpha synuclein and mitochondria. First of all, isogenic iPSCs represented by the loss of alpha synuclein were generated from its parental alpha synuclein triplication iPSCs, ND34391. The iPSCs were then differentiated into induced neurons. We demonstrated that overexpressed alpha synuclein resulted in an increased oxidative stress in the mitochondria but not when alpha synuclein was absent. We also observed that a shorter isoform of alpha synuclein is formed in the mitochondria using a HEK293T overexpression system. This shorter isoform could have been derived from a N-terminal truncation of the protein in the mitochondria. Altogether, our findings have provided an insight to alpha synuclein modulating ROS in the mitochondria. This provides preliminary evidences for further investigation about its interaction with mitochondrial proteins, which could explain the increase of oxidative stress and ultimately to the dysfunction of mitochondria.